Impact of genotype on clinical course in biventricular arrhythmogenic cardiomyopathy

Abstract

Aim. To analyze the correlation between genotype and phenotype in patients with biventricular arrhythmogenic right ventricular cardiomyopathy (ARVC).Methods. The clinical phenotype of 9 unrelated probands (89 % men, median age 35 [34; 37]) with biventricular ARVC were observed. The clinical and instrumental examination included a 12-lead ECG, 24-hour Holter ECG monitoring, transthoracic echocardiography and cardiac magnetic resonance imaging with late gadolinium enhancement. Biventricular variant of ARVC was diagnosed according to the 2020 Padua criteria for both right and left ventricles involvement. High-throughput sequencing was utilized to search for mutations in genes linked to the onset of cardiomyopathies and other inherited rhythm disorders. Statistical analysis procedures were performed using the STATISTICA-12 program.Results. In all patients with biventricular ARVC, according to late gadolinium enchansment magnetic resonance imaging, left ventricular involvement of varying degrees was detected, characterized by fibrous or fibrofatty infiltration of the myocardium, as well as regional or global systolic dysfunction. Genotyping in 9 patients with biventricular ARVC revealed 10 variants of the nucleotide sequence of III-V classes of pathogenicity according to the criteria of ACMG (2015) in 4 genes associated with ARVC (PKP2, DSP, DSC2, DSG2). Of these, 7 variants belonged to classes IV and V (PKP2 - 4 mutations, DSP - 2 mutations, DSG2 - 1 mutation); 3 nucleotide substitutions were variants with uncertain significance (VUS, class III) - 2 in DSC2 gene and 1 in DSP gene. A combination of nucleotide variants in two genes (DSP and DSC2) was detected in 1 patient. The findings highlight that mutations in DSP gene were associated with more severe systolic dysfunction and left ventricle dilation compared to carriers of mutations in PKP2 gene. In patients with variants of class III pathogenicity in DSC2 gene the most adverse clinical course of the disease was observed with the early onset of the first sustained ventricular tachycardia and the development of severe dysfunction and dilation of both ventricles requiring heart transplantation in comparison with carriers of mutations in other genes.Conclusion. The results obtained in a cohort of patients with biventricular ARVC demonstrate a specific correlation between genotype and clinical course and disease severity as well.